WO2011157445A1 - Marqueurs pour le pronostic et l'évaluation du risque d'hypertension gravidique et de prééclampsie - Google Patents

Marqueurs pour le pronostic et l'évaluation du risque d'hypertension gravidique et de prééclampsie Download PDF

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WO2011157445A1
WO2011157445A1 PCT/EP2011/003018 EP2011003018W WO2011157445A1 WO 2011157445 A1 WO2011157445 A1 WO 2011157445A1 EP 2011003018 W EP2011003018 W EP 2011003018W WO 2011157445 A1 WO2011157445 A1 WO 2011157445A1
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pro
pregnancy
preeclampsia
fragments
adm
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PCT/EP2011/003018
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English (en)
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Bruno Darbouret
Gaiané DEMIRDJIAN
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Cezanne S.A.S.
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Priority to JP2013514598A priority Critical patent/JP5684904B2/ja
Priority to US13/704,654 priority patent/US20130177901A1/en
Priority to EP11729558.4A priority patent/EP2583106A1/fr
Priority to RU2013102112/15A priority patent/RU2013102112A/ru
Priority to CN2011800301041A priority patent/CN103109192A/zh
Priority to BR112012032406A priority patent/BR112012032406A2/pt
Publication of WO2011157445A1 publication Critical patent/WO2011157445A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/02—Measuring pulse or heart rate
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/321—Arterial hypertension
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour

Definitions

  • the present invention is in the field of clinical diagnostics. Particularly the present invention relates to the prognosis and risk assessment in pregnant women to develop pregnancy-induced hypertension and/or preeclampsia by the determination of marker levels.
  • Hypertension is the most common medical problem encountered during pregnancy, complicating 2-3% of pregnancies. Hypertensive disorders during pregnancy are classified into 4 categories, as recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy: 1) chronic hypertension, 2) preeclampsia-eclampsia, 3) preeclampsia superimposed on chronic hypertension, and 4) gestational or pregnancy-induced hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy).
  • Chronic hypertension is defined as blood pressure exceeding 140/90 mm Hg before pregnancy or before 20 weeks' gestation. When hypertension is first identified during a woman's pregnancy and she is at less than 20 weeks' gestation, blood pressure elevations usually represent chronic hypertension.
  • preeclampsia occurs in up to 5% of all pregnancies, in 10% of first pregnancies, and in 20-25% of women with a history of chronic hypertension. Hypertensive disorders in pregnancy may cause maternal and fetal morbidity, and they remain a leading source of maternal mortality.
  • Gestational hypertension refers to hypertension with onset in the latter part of pregnancy (>20 weeks' gestation) without any other features of preeclampsia, and followed by normalization of the blood pressure postpartum. Of women who initially present with apparent gestational hypertension, about one third develops the syndrome of preeclampsia. As such, these patients should be observed carefully for this progression. The pathophysiology of gestational hypertension is unknown, but in the absence of features of preeclampsia, the maternal and fetal outcomes are usually normal. Gestational hypertension may, however, be a harbinger of chronic hypertension later in life.
  • Preeclampsia is a multi-system disorder in pregnancy, which is characterized by new onset of hypertension (systolic and diastolic blood pressure of > 140 and 90 mm Hg, respectively) and proteinuria (protein excretion of > 300 mg in a 24 h urine collection, or a dipstick of > 2+), that develop after 20 weeks of gestation in a previously normotensive women (Magee et al. 2008. J Obstet Gynecol Canada 30 (3) Suppl J.S1-S48).
  • Preeclampsia can have an early onset (starting before 34 weeks of gestation) or late onset (starting after 34 weeks of gestation).
  • preeclampsia can show mild or severe symptoms (systolic blood pressure ⁇ 160 mmHg or diastolic blood pressure ⁇ 1 10 mmHg, proteinuria >5 g/24 hours, oliguria, neurological symptoms, other clinical symptoms such as deranged liver function, thrombocytopenia ⁇ 100 000 mm 3 , HELLP syndrome), and can evolve in eclampsia in the most severe cases.
  • it can manifest as a maternal disorder only, with an appropriate fetal growing, or it can present itself with a growth restricted fetus (in utero growth restriction (RJGR)) or sudden fetal distress.
  • RJGR growth restricted fetus
  • Preeclampsia is more common at the extremes of maternal age ( ⁇ 18 y or >35 y).
  • the increased prevalence of chronic hypertension and other comorbid medical illnesses in women older than 35 years may explain the increased frequency of preeclampsia among older gravidas.
  • preeclampsia is primarily a disorder of placental dysfunction leading to a syndrome of endothelial dysfunction with associated vasospasm.
  • pathology demonstrates evidence of placental insufficiency with associated abnormalities such as diffuse placental thrombosis, an inflammatory placental decidual vasculopathy, and/or abnormal trophoblastic invasion of the endometrium. This supports abnormal placental development or placental damage from diffuse microthrombosis as being central to the development of this disorder.
  • Endothelial damage leads to pathologic capillary leak that can present in the mother as rapid weight gain, nondependent edema (face or hands), pulmonary edema, hemoconcentration, or a combination thereof.
  • the diseased placenta can also affect the fetus via decreased uteroplacental blood flow.
  • preeclampsia With or without IUGR, remains a major cause of maternal and neonatal mortality and morbidity worldwide.
  • VEGF vascular endoglin
  • PIGF vascular endoglin
  • sflt-1 soluble endoglin
  • P-selectin cell-free fetal DNA
  • ADAM 12 placental protein 13
  • PTX3 Pentraxin 3
  • PAPP- A pregnancy-associated plasma protein A
  • an imaging technique most widely used for predicting preeclampsia has been uteroplacental Doppler ultrasound. Impaired placental perfusion can be assessed by measuring flow waveform ratios or by detecting diastolic notching of the uterine arcuate vessels.
  • Adrenomedullin (ADM) and endothelin-1 (ET-1) are peptide hormones with vasoactive properties known to be present in the circulation. Both peptides are synthesized as larger prohormones and are released from their precursor peptides by proteolytical cleavage through peptide convertases. ADM and ET-1 were suggested to be implicated in the pathophysiology of hypertension (for review see: Murakami et al. 2006. Cardiovasc Hematol Disord Drug Targets 6(2): 125-132; Dhaun et al. 2008. Hypertension 52: 452-459). The role of ADM for the diagnosis of preeclampsia has already been investigated with contradictory results. Senna et al.
  • ET-1 levels were not statistically different between patients with pre-eclampsia and patients with normotensive uncomplicated pregnancy (Zunker et al. 1998. Fetal Diagn Ther. l 3(5):309-14). However, none of these studies investigated the use of ET-1 as a marker for the prognosis or risk assessment of a pregnant woman to develop preeclampsia.
  • Gao et al. 1996 could detect that, compared with matched normal pregnant women, plasma ET-1 levels were significantly increased, in pregnancy-induced hypertension patients. Significant positive correlations existed between plasma ET-1 level and mean arterial pressure or the score index of the severity of PIH ⁇ Gao et al. 1996. Chin Med J (Engl). 109(11):823-6). Zhang et al. 1994 revealed that the levels of ET-1 in hypertensive pregnancy were higher than those of the normal pregnancy ⁇ Zhang et al. 1994. Zhonghua Fu Chan Ke Za Zh.29(l l):645-7). However, in patients described in both Gao et al. and Zhang et al. ET-1 levels were measured at the time hypertension has already been manifested.
  • the inventors of the present invention have investigated whether the measurement of the levels of pro-ADM or fragments thereof and/or pro-ET-1 or fragments thereof, in particular, MR-pro-ADM and/or CT-pro-ET-1 levels, in a sample of a bodily fluid from a pregnant women could be used for the prognosis and risk assessment of pregnancy-induced hypertension and/or preeclampsia in these subjects.
  • the present invention relates to a method for the prognosis of development of pregnancy- induced hypertension and/or preeclampsia or risk assessment in pregnant women to develop pregnancy-induced hypertension and/or preeclampsia comprising the steps of:
  • fragments have a lengths of at least 6 amino acid residues.
  • Fig. 1 Box plot analysis for MR-pro-ADM
  • Fig. 2 Box plot analysis for CT-pro-ET-1
  • Fig. 3 ROC plot analysis for MR-pro-ADM to differentiate between controls and patients who will develop a late-onset preeclampsia
  • Fig. 4 ROC plot analysis for CT-pro-ET-1 to differentiate between controls and patients who will develop a late-onset preeclampsia
  • Fig. 5 ROC plot analysis for CT-pro-ET-1 to differentiate between controls and patients who will develop a pregnancy induced hypertension (PIH) - -
  • the present invention relates to a method for the prognosis of development of pregnancy- induced hypertension and/or preeclampsia or risk assessment in pregnant women to develop pregnancy-induced hypertension and/or preeclampsia comprising the steps of:
  • fragments have a lengths of at least 6 amino acid residues.
  • Said fragments have preferable a length of at least 6 amino acids, more preferably a length of at least 12 amino acid residues. Such fragments are preferably detectable with immunological assays as described herein.
  • a decrease of the level of pro-ADM or fragments thereof and/or pro-ET-1 or fragments thereof is indicative for an enhanced risk of pregnancy-induced hypertension and/or preeclampsia when compared with the level of pro-ADM or fragments thereof and/or pro-ET-1 or fragments thereof in sample from subjects not having a risk of pregnancy-induced hypertension and/or preeclampsia.
  • the measurement of pro-ADM or fragments thereof and/or pro-ET-1 or fragments thereof is carried out within the first to second trimester (8 th to 26 th week of pregnancy), more preferred within the first to early second trimester (8 th to 20 th week of pregnancy), even more preferred within the first trimester (8 th to 14 th week of pregnancy), mostly preferred within the early first trimester (8 th to 10 th week of pregnancy).
  • the measurement of pro-ADM or fragments thereof and/or pro- ET-1 or fragments thereof is carried out before 25 th week, preferably between 8 th and 24 th week of pregnancy.
  • the prognosis is related to an early onset (between 20 to 34 weeks of gestation) or a late onset (after 34 weeks of gestation) of preeclampsia.
  • further markers may additionally be determined selected from the group sflt-1 , sEng, PIGF, VEGF, PP-13, ADAM 12, P-Selectin, cell-free fetal DNA, PTX3, PAPP-A, visfatin, inhibin A, activin A, human chorionic gonadotropin (hCG), beta-hCG, alpha-fetoprotein (AFP), metalloproteinase-9 (MMP-9), ultrasound markers (uterine artery pulsatility index and/or diastolic notching) as well as pro-atrial natriuretic peptide (pro-ANP) or fragments thereof, pro-brain natriuretic peptide (pro-BNP) or fragments thereof and pro-Vas
  • said further markers are selected from the group comprising sflt-1 , sEng, PIGF, VEGF, PP-13, ADAM 12, P-Selectin, cell-free fetal DNA, PTX3, PAPP-A, visfatin, inhibin A, activin A, hCG, beta-hCG, AFP, MMP-9, ultrasound markers (uterine artery pulsatility index and/or diastolic notching), MR-proANP, NT-proBNP and Copeptin.
  • the invention also relates to the use of the described methods and kits for the prognosis and risk assessment of pregnancy-induced hypertension and/or preeclampsia in pregnant women.
  • gestational hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks of gestation (systolic and diastolic blood pressure of > 140 and 90 mm Hg, respectively).
  • preeclampsia includes a hypertensive, multi-system disorder of pregnant women, characterized by hypertension and proteinuria.
  • the most common symptoms of preeclampsia are high blood pressure, increased protein in the urine, and swelling or edema of hands and face.
  • preeclampsia is defined as hypertension (systolic and diastolic blood pressure of > 140 and 90 mm Hg, respectively) and proteinuria (protein excretion of > 300 mg in a 24 h urine collection, or a dipstick of > 2+).
  • the pregnancy-induced hypertension and/ or preeclampsia is asymptomatic and/or is not manifested at the time of measuring.
  • asymptomatic and/or not manifested means systolic and diastolic blood pressure of less than 140 and 90 mm Hg and/or protein excretion of less than 300 mg in a 24 h urine collection, or a dipstick of less than 2+.
  • test samples refers to a sample of bodily fluid obtained for the purpose of diagnosis, prognosis, or evaluation of a subject of interest, such as a patient.
  • Preferred test samples include blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, and pleural effusions.
  • one of skill in the art would realize that some test samples would be more readily analyzed following a fractionation or purification procedure, for example, separation of whole blood into serum or plasma components.
  • the sample is selected from the group consisting of a blood sample, a serum sample, a plasma sample, a cerebrospinal fluid sample, a saliva sample and an urine sample or an extract of any of the aforementioned samples.
  • the sample is a blood sample, most preferably a serum sample or a plasma sample.
  • the term "subject" as used herein refers to a living human or non-human organism.
  • the subject is a human subject that is pregnant within the first to second trimester (8 th to 26 th week of pregnancy), more preferred within the first to second trimester (8 th to 24 th week of pregnancy), even more preferred within the first to early second trimester (8 th to 20 th week of pregnancy), even more preferred within the first trimester (8 th to 14 th week of pregnancy), mostly preferred within the early first trimester (8 th to 10 th week of pregnancy),
  • the subject is a human subject that is pregnant within before 25 th week, preferably between 8 th and 24 th week of pregnancy.
  • correlating refers to comparing the presence or amount of the marker(s) in a patient to its presence or amount in persons known to suffer from, or known to be at risk of, a given condition.
  • a marker level in a patient sample can be compared to a level known to be associated with a specific diagnosis.
  • the sample's marker level is said to have been correlated with a diagnosis; that is, the skilled artisan can use the marker level to determine whether the patient suffers from a specific type diagnosis, and respond accordingly.
  • the sample ' s marker level can be compared to a marker level known to be associated with a good outcome (e.g. the absence of disease etc.).
  • a panel of marker levels is correlated to a global probability or a particular outcome.
  • fragment refers to smaller proteins or peptides derivable from larger proteins or peptides, which hence comprise a partial sequence of the larger protein or peptide. Said fragments are derivable from the larger proteins or peptides by saponification of one or more of its peptide bonds.
  • level in the context of the present invention relates to the concentration (preferably expressed as weight/ volume; w/v) of marker peptides taken from a sample of a patient.
  • Determining the level of pro-ADM or fragments thereof and/or pro-ET-1 or fragments thereof herein is performed using a detection method and/or a diagnostic assay.
  • a preferred pro-ADM fragment is MR-pro-ADM.
  • a preferred pro-ET-1 fragment is CT-pro-ET-1.
  • MR-pro-ADM has the following sequence:
  • ELRMSSSYPT GLADVKAGPA QTLIRPQDMK GASRSPEDSS CT-pro-ET-1 has the following sequence: SEQ ID No.2:
  • an “assay” or “diagnostic assay” can be of any type applied in the field of diagnostics. Such an assay may be based on the binding of an analyte to be detected to one or more capture probes with a certain affinity. Concerning the interaction between capture molecules and target molecules or molecules of interest, the affinity constant is preferably greater than 10 8 M "1 .
  • Capture molecules are molecules which may be used to bind target molecules or molecules of interest, i.e. analytes (i.e. in the context of the present - - invention the cardiovascular peptide(s)), from a sample. Capture molecules must thus be shaped adequately, both spatially and in terms of surface features, such as surface charge, hydrophobicity, hydrophilicity, presence or absence of lewis donors and/or acceptors, to specifically bind the target molecules or molecules of interest.
  • the binding may for instance be mediated by ionic, van-der-Waals, pi-pi, sigma-pi, hydrophobic or hydrogen bond interactions or a combination of two or more of the aforementioned interactions between the capture molecules and the target molecules or molecules of interest.
  • capture molecules may for instance be selected from the group comprising a nucleic acid molecule, a carbohydrate molecule, a RNA molecule, a protein, an antibody, a peptide or a glycoprotein.
  • the capture molecules are antibodies, including fragments thereof with sufficient affinity to a target or molecule of interest, and including recombinant antibodies or recombinant antibody fragments, as well as chemically and/or biochemically modified derivatives of said antibodies or fragments derived from the variant chain with a length of at least 12 amino acids thereof.
  • the preferred detection methods comprise immunoassays in various formats such as for instance radioimmunoassay (RIA), chemiluminescence- and fluorescence- immunoassays, Enzyme-linked immunoassays (ELISA), Luminex-based bead arrays, protein microarray assays, and rapid test formats such as for instance immunochromatographic strip tests.
  • RIA radioimmunoassay
  • ELISA Enzyme-linked immunoassays
  • Luminex-based bead arrays Luminex-based bead arrays
  • protein microarray assays protein microarray assays
  • rapid test formats such as for instance immunochromatographic strip tests.
  • the assays can be homogenous or heterogeneous assays, competitive and non-competitive assays.
  • the assay is in the form of a sandwich assay, which is a non-competitive immunoassay, wherein the molecule to be detected and/or quantified is bound to a first antibody and to a second antibody.
  • the first antibody may be bound to a solid phase, e.g. a bead, a surface of a well or other container, a chip or a strip
  • the second antibody is an antibody which is labeled, e.g. with a dye, with a radioisotope, or a reactive or catalytically active moiety.
  • the assay comprises two capture molecules, preferably antibodies which are both present as dispersions in a liquid reaction mixture, wherein a first labeling component is attached to the first capture molecule, wherein said first labeling component is part of a labeling system based on fluorescence- or chemiluminescence- quenching or amplification, and a second labeling component of said marking system is attached to the second capture molecule, so that upon binding of both capture molecules to the analyte a measurable signal is generated that allows for the detection of the formed sandwich complexes in the solution comprising the sample.
  • said labeling system comprises rare earth cryptates or rare earth chelates in combination with fluorescence dye or chemiluminescence dye, in particular a dye of the cyanine type.
  • fluorescence based assays comprise the use of dyes, which may for instance be selected from the group comprising FAM (5-or 6- carboxyfluorescein), VIC, NED, Fluorescein, Fluoresceinisothiocyanate (FITC), IRD- 700/800, Cyanine dyes, such as CY3, CY5, CY3.5, CY5.5, Cy7, Xanthen, 6-Carboxy- 2',4',7',4,7-hexachlorofluorescein (HEX), TET, 6-Carboxy-4',5'-dichloro-2',7'-dimethody- fluorescein (JOE), N,N,N',N'-Tetramethyl-6-carboxyrhodamine (TAMRA), 6-Carboxy-X- rhodamine (ROX), 5-Carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), Rho
  • chemiluminescence based assays comprise the use of dyes, based on the physical principles described for chemiluminescent materials (Kirk-Othmer, Encyclopedia of chemical technology, 4th ed., executive editor, J. I. Kroschwitz; editor, M. Howe-Grant, John Wiley & Sons, 1993, vol.15, p. 518-562, incorporated herein by reference, including citations on pages 551-562).
  • Preferred chemiluminescent dyes are acridiniumesters.
  • ROC curves Receiver Operating Characteristic curves
  • a threshold is selected, above which (or below which, depending on how a marker changes with the disease) the test is considered to be abnormal and below which the test is considered to be normal.
  • the area under the ROC curve is a measure of the probability that the perceived measurement will allow correct identification of a condition.
  • a threshold is selected to provide a ROC curve area of greater than about 0.5, more preferably greater than about 0.7, still more preferably greater than about 0.8, even more preferably greater than about 0.85, and most preferably greater than about 0.9.
  • the term "about” in this context refers to +/- 5% of a given measurement.
  • the horizontal axis of the ROC curve represents (1 -specificity), which increases with the rate of false positives.
  • the vertical axis of the curve represents sensitivity, which increases with the rate of true positives.
  • the value of (1 -specificity) may be determined, and a corresponding sensitivity may be obtained.
  • the area under the ROC curve is a measure of the probability that the measured marker level will allow correct identification of a disease or condition. Thus, the area under the ROC curve can be used to determine the effectiveness of the test.
  • markers and/or marker panels are selected to exhibit at least about 70% sensitivity, more preferably at least about 80% sensitivity, even more preferably at least about 85% sensitivity, still more preferably at least about 90% sensitivity, and most preferably at least about 95% sensitivity, combined with at least about 70% specificity, more preferably at least about 80% specificity, even more preferably at least about 85% specificity, still more preferably at least about 90% specificity, and most preferably at least about 95% specificity.
  • both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about - -
  • the development of a pregnancy-induced hypertension and/or preeclampsia is predicted in a pregnant woman when said determined level of MR-pro-ADM is lower than a predetermined threshold level.
  • the predetermined threshold level of MR-pro-ADM is between 0.2 and 0.6 nmol/L, more preferably between 0.2 nmol/L and 0.5 nmol/L, even more preferred between 0.2 nmol/L and 0.4 nmol/L, most preferred between 0.2 nmol/L and 0.3 nmol/L.
  • the development of a pregnancy-induced hypertension and/or preeclampsia is predicted in a pregnant woman when said determined level of MR-pro-ADM or fragments thereof is lower than 0.6 nmol/L, preferably lower than 0.5 nmol/L, more preferably lower than 0.4 nmol/L, most preferred lower than 0.3 nmol/L.
  • the development of a pregnancy-induced hypertension and/or preeclampsia is predicted in a pregnant woman when said determined level of CT-pro-ET-1 or fragments thereof is lower than a predetermined threshold level.
  • the predetermined threshold level of CT-pro-ET-1 or fragments thereof is between 20 and 60 pmol/L, more preferably between 20 pmol/L and 50 pmol/L, even more preferred between 20 pmol/L and 40 pmol/L, most preferred between 20 pmol/L and 30 pmol/L.
  • the development of a pregnancy-induced hypertension and/or preeclampsia is predicted in a pregnant woman when said determined level of CT-pro-ET-1 or fragments thereof is lower than 60 pmol/L, preferably lower than 50 pmol/L, more preferably lower than 40 pmol/L, most preferred lower than 30 pmol/L.
  • EDTA-samples were taken at the time of each prenatal visit, which is held at 1 1 to 14 weeks of gestation. At that time all patients included into the study were asymptomatic and did not show any signs or symptoms for preeclampsia or PIH. All pregnant women signed a consent form approved by King's College Hospital Ethics Committee.
  • a patient was diagnosed to suffer from preeclampsia if hypertension (systolic or diastolic blood pressure of > 140 and 90 mm Hg, respectively) and proteinuria (protein excretion of > 300 mg in a 24 h urine collection, or a dipstick of > 2+) was detected after 20 weeks of gestation.
  • Patients with the diagnosis of preeclampsia were further classified according to the time of preeclampsia onset as early-onset preeclampsia (onset of symptoms between week 20 and 34 of gestation) and late-onset preeclampsia (onset of symptoms after 34 weeks of gestation).
  • a patient was diagnosed to suffer from PIH if the diastolic blood pressure of > 90 mm Hg was detected on >2 occasions 4 hours apart after 20 weeks of gestation in previously normotensive women in the absence of significant proteinuria.
  • MR-pro-ADM and CT-pro-ET-1 were detected using novel fully automated sandwich immunoassay systems on the B.R.A.H.M.S KRYPTOR (B.R.A.H.M.S GmbH, Hennigsdorf/ Berlin, Germany) ⁇ Caruhel et al. 2009. Clin Biochem 42: 725-8).
  • This random access analyzer employs the sensitive Time Resolved Amplified Cryptate Emission (TRACE) technology, based on a non-radioactive- transfer between 2 fluorophores, europium cryptate and XL665.
  • TRACE Time Resolved Amplified Cryptate Emission
  • the automated assay for the detection of MR-pro-ADM is based essentially on the sandwich fluorescence assay using the same antibody pair as described in detail elsewhere (Morgenthaler et al. 2005 Clin Chem 51:1823-9).
  • 26 ⁇ plasma was incubated for 29 min.
  • the measuring range was 0-100 nmol/L, the limit of detection and limit of quantification were 0.05 and 0.23 nmol/L, respectively.
  • the intra assay CV was 1.9 % and the inter laboratory CV was 9.8 % at 1.17 nmol/L.
  • the automated sandwich fluorescence assay for the detection of CT-proET-1 uses a mouse monoclonal antibody directed against a peptide comprising the amino acids 167 to 183 of the human pro-ET-1 sequence (SEQ. ID No. 3) and a sheep polyclonal antibody directed against a peptide comprising the amino acids 183 to 195 of the human pro-ET-1 sequence (SEQ. ID No. 4).
  • 50 ⁇ plasma was incubated for 24 min.
  • the measuring range of the assay was 0-500 pmol/L, the limit of detection and limit of quantification were 2.8 and 9.78 pmol/L, respectively.
  • the intra- and inter-assay CV determined in the range of 44-324 pmol/L were 1.3-4.6% and 6.3-9.6%, respectively (Caruhel et al. 2008 AACC 54:6, Supplement A 119/C-63, abstract).
  • CT-pro-ET-1 levels were significantly lower in women who developed a late-onset preeclampsia when compared to pregnant controls (p ⁇ 0.03). Moreover, the CT-pro-ET-1 concentration was significantly lower in women who developed pregnancy-induced hypertension (p ⁇ 0.03) in comparison to pregnant non-hypertensive controls.
  • AUC area under the ROC curve
  • the sensitivities and specificities of exemplary CT-pro-ET-1 cut-off values to differentiate between pregnant non-hypertensive controls and women who will develop late-onset preeclampsia are given in table 3.
  • CT-pro-ET-1 The AUC for CT-pro-ET-1 to differentiate between pregnant non-hypertensive controls and women who will develop PIH was 0.64 (p ⁇ 0.03) (see Fig. 5).
  • the sensitivities and specificities of exemplary CT-pro-ET-1 cut-off values to differentiate between pregnant non-hypertensive controls and women who will develop PIH are given in table 4.
  • CT-pro-ET-1 cut-off value (pmol/L) Specificity (in %) Sensitivity (in %)

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Abstract

L'invention porte sur le pronostic et l'évaluation du risque, chez la femme enceinte, de développer une hypertension gravidique et/ou une prééclampsie par détermination des niveaux de marqueurs.
PCT/EP2011/003018 2010-06-18 2011-06-17 Marqueurs pour le pronostic et l'évaluation du risque d'hypertension gravidique et de prééclampsie WO2011157445A1 (fr)

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JP2013514598A JP5684904B2 (ja) 2010-06-18 2011-06-17 妊娠高血圧症及び子癇前症の予後診断とリスクの評価のためのマーカー
US13/704,654 US20130177901A1 (en) 2010-06-18 2011-06-17 Markers for the prognosis and risk assessment of pregnancy-induced hypertension and preeclampsia
EP11729558.4A EP2583106A1 (fr) 2010-06-18 2011-06-17 Marqueurs pour le pronostic et l'évaluation du risque d'hypertension gravidique et de prééclampsie
RU2013102112/15A RU2013102112A (ru) 2010-06-18 2011-06-17 Маркеры для прогнозирования и оценки риска развития обусловленных беременностью гипертензии и преэклампсии
CN2011800301041A CN103109192A (zh) 2010-06-18 2011-06-17 用于妊娠性高血压和先兆子痫的预后和风险评估的标志物
BR112012032406A BR112012032406A2 (pt) 2010-06-18 2011-06-17 marcadores para o prognóstico e avaliação de risco de hipertensão induzida pela gravidez e pré-eclâmpsia

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WO2014124392A1 (fr) * 2013-02-08 2014-08-14 University Of Iowa Research Foundation Outils de diagnostic pour prédire l'apparition de pré-éclampsie
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RU2565405C1 (ru) * 2014-05-07 2015-10-20 Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") СПОСОБ ПРОГНОЗИРОВАНИЯ УРОВНЯ АРТЕРИАЛЬНОГО ДАВЛЕНИЯ У ЖЕНЩИН НА СРОКЕ РОДОРАЗРЕШЕНИЯ С ИСПОЛЬЗОВАНИЕМ ГЕНЕТИЧЕСКОГО ПОЛИМОРФИЗМА 4a/4b eNOS
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WO2021009260A1 (fr) * 2019-07-15 2021-01-21 University Of Tartu Méthode de pronostic et de diagnostic de la pré-éclampsie
RU2741730C1 (ru) * 2020-10-12 2021-01-28 Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермский государственный медицинский университет имени академика Е.А. Вагнера" Министерства здравоохранения Российской Федерации Способ прогнозирования риска развития тяжелых осложнений преэклампсии
RU2753463C1 (ru) * 2021-02-28 2021-08-16 федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет) (ФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Се Способ прогнозирования тяжести течения ранней преэклампсии
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WO2014078622A1 (fr) * 2012-11-15 2014-05-22 The Brigham And Women's Hospital, Inc. Procédé et système pour diagnostiquer et traiter la prééclampsie
WO2014124392A1 (fr) * 2013-02-08 2014-08-14 University Of Iowa Research Foundation Outils de diagnostic pour prédire l'apparition de pré-éclampsie
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RU2565405C1 (ru) * 2014-05-07 2015-10-20 Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") СПОСОБ ПРОГНОЗИРОВАНИЯ УРОВНЯ АРТЕРИАЛЬНОГО ДАВЛЕНИЯ У ЖЕНЩИН НА СРОКЕ РОДОРАЗРЕШЕНИЯ С ИСПОЛЬЗОВАНИЕМ ГЕНЕТИЧЕСКОГО ПОЛИМОРФИЗМА 4a/4b eNOS
WO2017180876A1 (fr) * 2016-04-13 2017-10-19 Abbott Laboratories Détection de troponine i cardiaque pendant une grossesse pour une identification de maladie cardiovasculaire et une évaluation de risque
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EP3730944A1 (fr) * 2016-04-13 2020-10-28 Abbott Laboratories Détection de troponine i cardiaque pendant la grossesse pour l'identification de maladies cardiovasculaires et d'évaluation de risques
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WO2018191406A1 (fr) * 2017-04-11 2018-10-18 University Of Iowa Research Foundation Détection de prédicteurs de prééclampsie
RU2691114C1 (ru) * 2018-03-20 2019-06-11 федеральное государственное бюджетное образовательное учреждение высшего образования "Ростовский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ прогнозирования развития преэклампсии в поздние сроки беременности
WO2021009260A1 (fr) * 2019-07-15 2021-01-21 University Of Tartu Méthode de pronostic et de diagnostic de la pré-éclampsie
RU2741730C1 (ru) * 2020-10-12 2021-01-28 Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермский государственный медицинский университет имени академика Е.А. Вагнера" Министерства здравоохранения Российской Федерации Способ прогнозирования риска развития тяжелых осложнений преэклампсии
RU2753463C1 (ru) * 2021-02-28 2021-08-16 федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет) (ФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Се Способ прогнозирования тяжести течения ранней преэклампсии
WO2022234111A1 (fr) * 2021-05-07 2022-11-10 Sphingotec Gmbh Adrénomédulline mature permettant une stratification thérapeutique de corticostéroïdes chez des patients gravement malades
RU2808924C1 (ru) * 2023-03-16 2023-12-05 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Способ прогнозирования риска развития преэклампсии у беременных с задержкой роста плода

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US20130177901A1 (en) 2013-07-11
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